Pathophysiology and management of hepatic encephalopathy 2014 update: Ammonia toxicity and hyponatremia

Abstract

Hyperammonemia is a major factor involved in the pathogenesis of hepatic encephalopathy (HE). Ammonia elicits astrocyte swelling and causes brain edema. In addition, hyponatremia, a condition frequently observed in hepatic cirrhosis, also exacerbates brain edema, potentially becoming a factor that exacerbates HE. Therefore, as a treatment strategy for HE, alleviating ammonia toxicity is essential. In addition to restricting protein intake, synthetic disaccharides such as lactulose and lactitol, probiotics that improve gut flora, and rifaximin, an antibiotic with poor bioavailability, are also administrated. Additionally, branched-chain amino acids and carnitine have also been administrated. Moreover, we investigated the current trend in the concomitant use of drugs with different mechanisms of action. In Japan, the V2 receptor antagonist tolvaptan can be administrated to hepatic cirrhosis patients with fluid retention. This drug is also useful as a countermeasure for hyponatremia in hepatic cirrhosis, and elucidating its effects in HE patients may therefore become an agenda in the future. These observations indicate that ammonia toxicity, gut flora control and low sodium control are major focuses in HE improvement and long-term prognosis.

Hepatic encephalopathy due to liver cirrhosis

“…Hyponatraemia, common in cirrhosis, may also exacerbate cerebral oedema and astrocyte dysfunction. 28 Muscle volume depletion (sarcopenia) contributes to the development of encephalopathy, since muscle represents an alternative site of ammonia detoxification. 29 Patients with a concomitant systemic inflammatory response syndrome, such as from infection, are predisposed to developing hepatic encephalopathy.…”

Perioperative Risk Assessment and Management of Cirrhotic Patients

“…Patients with hepatic encephalopathy (HE) exhibit psychomotor, cognitive, emotional, behavioral, and motor skill dysfunction (Table 1) [82]. Ammonia, a neurotoxin [83] that impairs nutrient transport into neurons and astrocytes, metabolism of amino acids, brain energy consumption, and nerve potential transmission, is produced by intestinal bacteria metabolic effect on proteins, purines, and urea [84].…”

“…In LC, due to portosystemic shunts formation and decreased liver function, circulating ammonia triggers secondary organ detoxification mechanisms in the brain, skeletal muscles, and kidneys [84]. The latter two activate normally inactivated enzymes, including glutamine synthetase and glutaminase [85], while the only CNS cells capable of detoxification, astrocytes, produce high amounts of the osmotic regulator glutamine resulting in edema [82,86]. When these mechanisms fail or become saturated, ammonia reaches toxic levels resulting in HE [68,82], often precipitated or worsened by surgery and anesthesia [1,32].…”

“…The latter two activate normally inactivated enzymes, including glutamine synthetase and glutaminase [85], while the only CNS cells capable of detoxification, astrocytes, produce high amounts of the osmotic regulator glutamine resulting in edema [82,86]. When these mechanisms fail or become saturated, ammonia reaches toxic levels resulting in HE [68,82], often precipitated or worsened by surgery and anesthesia [1,32]. HE can be complicated by unnecessary workup and sub-optimal recovery including immobility, inability to comply with physical therapy, and aspiration [32].…”

Prevalence of Helicobacter pylori Infection in Patients with Minimal Hepatic Encephalopathy

“…Our picture of the pathogenesis and development of HE is still incomplete, but ammonia is considered to be most relevant [7,8]. Treatments with non-absorbable antibiotics and non-absorbable disaccharides aim at the reduction of bacterial ammonia production in the large bowel and have been proven to be effective against MHE.…”